Methods for reducing the risk of an adverse dronedarone / beta-blockers interaction in a patient suffering from atrial fibrilation

ABSTRACT

The disclosure relates to a method for managing the risk of dronedarone/beta-blockers interaction by using dronedarone or pharmaceutically acceptable salts thereof in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted to reduce the risk of cardiovascular hospitalization, said patients also expecting to receive a beta-blockers treatment, by performing the following steps:
         a—initiate beta-blockers treatment at a low dose;   b—performing a electrocardiogram (ECG) verification of good tolerability;   c—increase of beta-blockers dose only if results in step b) are satisfying.

The present invention relates to the use of dronedarone or pharmaceutically acceptable salts thereof, for the preparation of a medicament for use in the prevention of atrial fibrillation, and reducing the risk of an adverse drug interaction with beta-blockers such as metoprolol and propranolol.

The instant invention relates to a method of providing dronedarone or pharmaceutically acceptable salts thereof.

The instant invention also relates to a method of managing the risk of beta-blockers/dronedarone interaction.

The instant invention also relates to a method of promoting the use of dronedarone or pharmaceutically acceptable salts or esters thereof.

The instant invention also relates to an article of manufacture and a package comprising dronedarone or pharmaceutically acceptable salts or esters thereof.

2-n-Butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulphonamidobenzofuran, or dronedarone, and pharmaceutically acceptable salts thereof are described in European Patent EP 0 471 609 B1.

Dronedarone blocks potassium, sodium and calcium channels and also has anti-adrenergic properties. Dronedarone is an antiarrhythmic that is effective in maintaining sinus rhythm in patients presenting atrial fibrillation or atrial flutter.

The applicant has clinically proven that dronedarone significantly reduces cardiovascular hospitalizations and/or mortality in patients having a history of atrial fibrillation (AF) or of atrial flutter (AFL) in a safe and effective way. Dronedarone is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent AF or AFL, with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter >50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted.

Beta-blockers, commonly prescribed drugs in cardiac patients, are mainly metabolized by CYP2D6. Interactions due to inhibition of beta-blockers metabolism by CYP2D6 inhibitors have been reported. Dronedarone has the potential to inhibit CYP2D6.

Beta-blockers are frequently co-prescribed as they are used for the treatment of hypertension, cardiac arrhythmias, coronary ischemia in particular post-myocardial infarction and heart failure. The coadministration of dronedarone and beta-blockers may result in an interaction that may lead to side effects such as bradycardia, heart failure and fatigue if not carefully managed. Based on the likelihood of the co-prescription of these 2 drugs and the likelihood of clinically significant interactions, an interaction study was performed.

During an interaction study with dronedarone, it has been observed that administration of this active principle together with beta-blockers is associated with an increase of steady state beta-blockers exposures, which can lead to side effects such as bradycardia, heart failure and fatigue.

The Applicant has now found the regimen to administrate dronedarone to patients in a safe and effective way, those patients expecting to receive beta-blockers. Consequently, they found methods for managing the risk related to beta-blockers/dronedarone interaction.

The methods according to the invention enable a method to decrease the risk of such an event, when dronedarone or pharmaceutically acceptable salts or esters thereof is administered for treating patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≧50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted.

The present invention relates to the use of dronedarone or pharmaceutically acceptable salts thereof in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≧50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted to reduce the risk of cardiovascular hospitalization, said patients also expecting to receive a beta-blockers treatment, by performing the following steps

-   -   a—initiate beta-blockers treatment at a low dose;     -   b—performing electrocardiogram (ECG) verification of good         tolerability;     -   c—increase beta-blockers dose only if results in step b) are         satisfying.

The present invention also relates to a method for managing the risk of dronedarone/beta-blockers interaction by using dronedarone or pharmaceutically acceptable salts thereof in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≧50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted to reduce the risk of cardiovascular hospitalization, said patients also expecting to receive a beta-blockers treatment, by performing the following steps:

-   -   a—initiate beta-blockers treatment at a low dose;     -   b—performing ECG verification of good tolerability;     -   c—increase of beta-blockers dose only if results in step b) are         satisfying.

In the instant invention, beta-blockers may be metoprolol or propranolol.

In some embodiments, dronedarone is administered 400 mg twice daily with meals.

In some embodiments a pharmaceutically acceptable salt of dronedarone is hydrochloride.

In step a), the term “low dose of beta-blockers” as used herein means a fraction of the recommended dose. In any case, this low dose is patient-dependent and may be defined taking into account individual patient's characteristics.

For example, a low dose may be

-   -   for metoprolol, less than 200 mg e.g. as 100 mg;     -   for propranolol, less than 160 mg, e.g. as 40 mg.

In step b), “ECG verification of good tolerability” and “ECG assessment” has the same meaning, i.e. assessments have to be made regarding for example heart rate, PR- and QTc-interval duration. For example heart rate may be higher than 50 bpm, PR-interval may be shorter than 200 ms.

In step c), increase or uptitration of beta-blockers will be a fraction of the recommended dose higher than the low dose as defined above up to a maximum dose of:

-   -   200 mg for metoprolol,     -   320 mg for propranolol.

The recommended dose is the dose defined in the labelling of the beta-blockers.

The maximum dose is defined according to the labelling of the beta-blockers.

The term “cardiovascular hospitalization” means a hospitalization which is caused by at least one of the following pathologies (Hohnloser et al., Journal of cardiovascular electrophysiology, January 2008, vol. 19, No. 1, pages 69-73):

-   -   relating to atherosclerosis,     -   myocardial infarction or unstable angina pectoris,     -   stable angina pectoris or atypical thoracic pain,     -   syncope,     -   transient ischemic event or cerebral stroke (except intracranial         haemorrhage),     -   atrial fibrillation and other supraventricular rhythm disorders,     -   non-fatal cardiac arrest,     -   ventricular arrhythmia,     -   cardiovascular surgery, except heart transplant,     -   heart transplant,     -   implantation of a cardiac stimulator (pacemaker), of an         implantable defibrillator (“ICD”) or of another cardiac device,     -   percutaneous coronary, cerebrovascular or peripheral         intervention,     -   variations in arterial pressure (hypotension, hypertension,         except syncope),     -   cardiovascular infection,     -   major bleeding/haemorrhage (requiring two or more blood cell         pellets or any intracranial haemorrhage),     -   pulmonary embolism or deep vein thrombosis,     -   worsening of congestive heart failure including acute pulmonary         oedema or dyspnoea from cardiac causes.

Consequently, the prevention of cardiovascular hospitalization may be understood as the prevention of cardiovascular hospitalization for at least one of the above mentioned pathologies.

The present invention also relates to a method of providing dronedarone or pharmaceutically acceptable salts or esters, wherein said dronedarone or pharmaceutically acceptable salts or esters thereof is provided along with information indicating that it is useful for treating patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≧50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted to reduce the risk of cardiovascular hospitalization, and in case said patients also expecting to receive a beta-blockers treatment, the following steps should be observed:

-   -   a—initiate beta-blockers treatment at a low dose;     -   b—performing ECG verification of good tolerability;     -   c—increase of beta-blockers dose only if results in step b) are         satisfying.

In some embodiments, a pharmaceutically acceptable salt of dronedarone is hydrochloride.

In some embodiments, the information comprises printed matter that advises that dronedarone or pharmaceutically acceptable salts or esters thereof is useful for treating patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter >50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted to reduce the risk of cardiovascular hospitalization, and in case said patients also expecting to receive a beta-blockers treatment, the following steps should be observed:

-   -   a—initiate beta-blockers treatment at a low dose;     -   b—performing ECG verification of good tolerability;     -   c—increase of beta-blockers dose only if results in step b) are         satisfying.

The present invention also concerns a method of promoting the use of dronedarone or pharmaceutically acceptable salts or esters thereof, the method comprising the step of conveying to a recipient at least one message comprising dronedarone or pharmaceutically acceptable salts or esters thereof is useful for treating patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≧50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted to reduce the risk of cardiovascular hospitalization, and in case said patients also expecting to receive a beta-blockers treatment, the following steps should be observed:

-   -   a. initiate beta-blockers treatment at a low dose;     -   b. performing ECG verification of good tolerability;     -   c. increase of beta-blockers dose only if results in step b) are         satisfying.

In some embodiments a pharmaceutically acceptable salt of dronedarone is hydrochloride. The instant invention also concerns an article of manufacture comprising

-   -   a) a packaging material;     -   b) dronedarone or pharmaceutically acceptable salts or esters         thereof or, and     -   c) a label or package insert contained within the packaging         material indicating that:

i) dronedarone or pharmaceutically acceptable salts or esters thereof is indicated in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≧50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted to reduce the risk of cardiovascular hospitalization, and

ii) in case said patients also expecting to receive a beta-blockers treatment, the following steps should be observed:

-   -   d. initiate beta-blockers treatment at a low dose;     -   e. performing ECG verification of good tolerability;     -   f. increase of beta-blockers dose only if results in step b) are         satisfying.

In some embodiments a pharmaceutically acceptable salt of dronedarone is hydrochloride.

The invention also concerns a package comprising dronedarone or pharmaceutically acceptable salts or esters thereof and a label, said label comprising a printed statement which informs a prospective user that:

i) dronedarone or pharmaceutically acceptable salts or esters thereof is indicated in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≧50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted to reduce the risk of cardiovascular hospitalization, and

ii) in case said patients also expecting to receive a beta-blockers treatment, the following steps should be observed:

-   -   a. initiate beta-blockers treatment at a low dose;     -   b. performing ECG verification of good tolerability;     -   c. increase of beta-blockers dose only if results in step b) are         satisfying.

In some embodiments a pharmaceutically acceptable salt of dronedarone is hydrochloride.

The invention also relates to a method for administering a combination of beta-blockers and dronedarone or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein said method comprises the following steps:

-   -   a. initiate beta-blockers treatment at a low dose;     -   b. performing ECG verification of good tolerability;     -   c. increase of beta-blockers dose only if results in step b) are         satisfying.

In some embodiments a pharmaceutically acceptable salt of dronedarone is hydrochloride

The term “pharmaceutically acceptable salts” as used herein means that the salts of the compounds of the present invention can be used in medicinal preparations. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, salicylic acid, cinnamic acid, 2-phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid. The acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate can also be formed. Also, the salts so formed may present either as mono- or di-acid salts and can exist substantially anhydrous or can be hydrated. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts, and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.

It will also be specified that the expression “patients having a history of atrial fibrillation or atrial flutter”, “patients with a history of or a current atrial fibrillation or flutter” or “patients with a recent history of or a current atrial fibrillation or flutter” or “patients with paroxysmal or persistent atrial fibrillation or flutter” or “patients with a history of, or a current paroxysmal or persistent atrial fibrillation or flutter” or “patients with a recent history of, or a current paroxysmal or persistent atrial fibrillation or flutter” or “patients with paroxysmal or intermittent atrial fibrillation or atrial flutter and a recent episode of atrial fibrillation or atrial flutter, who are in sinus rhythm or who will be cardioverted” or “patients with paroxysmal or persistent atrial fibrillation or atrial flutter and a recent episode of atrial fibrillation or atrial flutter, who are in sinus rhythm or who will be cardioverted” means a patient who, in the past, has presented one or more episodes of atrial fibrillation or flutter and/or who is suffering from atrial fibrillation or atrial flutter at the time the dronedarone or a pharmaceutically acceptable salt thereof is used. More particularly, this expression means patients with documentation of having been in both atrial fibrillation or flutter and sinus rhythm within the last 6 months preceding the start of treatment. Patients could be either in sinus rhythm, or in atrial fibrillation or flutter at the time the dronedarone or a pharmaceutically acceptable salt thereof is initiated.

The instant invention is further illustrated by the clinical data below.

EXAMPLE 1

This was a monocenter, randomized, double-blind, placebo-controlled, repeated dose, dose-escalating study in healthy male caucasian subjects, aged 25-40 years.

Subjects received metoprolol 200 mg OD alone for 5 days followed immediately by dronedarone 400 mg BID (Group 1), 600 mg BID (Group 2) or 800 mg BID (Group 3) and metoprolol 200 mg OD co-administration for 8 additional days. All treatments were administered in fed conditions. Blood samples were collected at trough before treatment and during the repeated administration, then over 12 h after the last dronedarone dose for dronedarone/SR35021 analysis, and up to 24 h after the last metoprolol dose for metoprolol/alpha-hydroxymetoprolol analysis.

Plasma dronedarone/SR35021 concentrations were determined using a validated liquid chromatography-mass spectrometry method, metoprolol and alpha-hydroxymetoprolol plasma concentrations were assessed using a validated High Performance Liquid Chromatography (HPLC) method with fluorescence detection.

Statistical Analysis

Pharmacokinetic parameters and before treatment concentrations on Day 5 and Day 13 were summarized using standard descriptive statistics. For dronedarone and SR35021, the dose effects were tested on Day 13 by ANOVA, using log transformed values. For metoprolol and alpha-hydroxymetoprolol, the dose effects were analyzed by ANOVA, using log transformed values and rank transformed values; if a group effect emerged, the Dunnet test was performed.

Day 13/Day 5 ratios, 90% and 95% CIs were also calculated.

Continuous demographic variables were summarized using standard descriptive statistics, qualitative variables summarized by count and percents.

The pharmacodynamic analyses were based on the change in Day 5 and Day 13 measurements, using a one-way analysis of variance (ANOVA) model with term for dose, for both primary and secondary endpoints; estimates and 95% confidence intervals (CI) of the difference in mean CHGDay13-5 between dronedarone dose groups and the placebo group were derived within the ANOVA framework. As the sample size calculation was based on the comparison of the highest dronedarone dose versus placebo, pairwise comparison were performed without adjustment of the overall treatment first type error rate.

Safety evaluation was based upon a review of individual values and descriptive statistics (listings, summary tables, graphics).

Results

Mean (SD) values of pharmacokinetic parameters of metoprolol, alone and co-administered with dronedarone, and Day 5/Day 13 ratio estimates and confidence intervals are shown in table 1:

Dronedarone/Placebo treatment Mean (SD) 800 mg/day Parameters Placebo (n = 11) (b.i.d) n = 4 Metoprolol alone (day 5) C_(min) (ng/mL) 30.3 (43.4) 27.9 (17.5) C_(max) (ng/mL) 100.6 (86.4)  92.7 (39.8) t_(max) (h)* 5.0 4.0 AUC₀₋₂₄ 1541 (1563) 1555 (803)  (ng · h/mL) Metoprolol + dronedarone (day 13) C_(min) (ng/mL) 36.3 (44.5) 41.8 (26.6) C_(max) (ng/mL) 134.1 (96.8)  162.6 (55.5)  t_(max) (h)* 5.0 5.0 AUC₀₋₂₄ 1862 (1689) 2318 (846)  (ng · h/mL) Ratio estimates (day 13/day 5) and 90% CI C_(max) (ng/mL) 1.34 [1.08-1.66] 1.84 [1.29-2.64] AUC₀₋₂₄ 1.29 [1.08-1.55] 1.63 [1.21-2.20] (ng · h/mL)

Whatever the administered dronedarone dose the metoprolol C_(max) and AUC_(0-24h) were significantly higher after 8 days of treatment.

As a function of the dronedarone administered dose, the effect tended to be higher:

-   1.8-fold increase in C_(max) -   1.6-fold increase in AUC₀₋₂₄

There was a statistically significant reduction in Vcfmean (−0.28 s-1, p=0.0002), when dronedarone 800 mg BID was added on top of metoprolol 200 mg OD, indicating a reduction in myocardial contractility. Results on other contractility parameters using a different technique showed a similar trend.

Conclusion

Plasma metoprolol exposure at steady-state was increased by 1.6-fold after concomitant administration of therapeutic dose of dronedarone for 8 days.

At 400 mg BID, dronedarone increased steady-state metoprolol (200 mg OD) exposures by 1.6-fold, without significant effect on alpha hydroxymetoprolol exposures, in CYP2D6 extensive metabolizer subjects and is therefore a weak inhibitor of CYP2D6 in vivo. The interaction ratio is lower than the existing 3-(C_(max)) to 6-fold (AUC) difference in metoprolol exposure between poor and extensive CYP2D6 metabolizers.

The above study is reported in Damy and al, Fundamental & Clinical Pharmacology, 18 (2004), 113-123 which is incorporated herein by reference.

EXAMPLE 2

This was a monocenter, open-label, non-placebo controlled study performed under Good Clinical Practice in healthy male subjects.

Subjects received dronedarone 800 mg OD alone, propranolol 80 mg OD alone, dronedarone and propranolol co-administration at same regimens described above for 7 days. All treatments were administered in fed conditions. Blood samples were collected at trough before and during the repeated administration, then over 12 h after the last dronedarone dose for dronedarone/SR35021 for dronedarone/SR35021 analysis, and up to 24 h after the last propranolol dose for propranolol analysis.

Plasma dronedarone/SR35021 concentrations were determined using a validated High Performance Liquid Chromatography (HPLC) with ultraviolet detection method, metoprolol plasma concentrations were assessed using a validated fluorimetric detection method.

Statistical Methods

Pharmacokinetics: Propranolol, dronedarone and SR35021 C_(bt) values were analyzed using repeated measures analysis of variance to assess “day” effects after repeated dosing. If a “day” effect was statistically significant, iterative analyses were performed without the earliest C_(bt) until a non-significant effect was obtained; steady-state was assumed as soon as the “day” effect was non-significant. Propranolol C_(bt) values after dosing with propranolol alone were compared to those obtained after dosing with dronedarone plus propranolol for “day”, “treatment” and “day-by-treatment” effects. Propranolol C_(max′) AUC_(0-12′) and AUC_(last) values were logarithmically transformed and analyzed for “treatment” effects of single and repeated dosing of propranolol versus dronedarone plus propranolol. dronedarone and SR35021 C_(max) and AUC₀₋₂₄ values were analyzed to compare the “treatment” effect of a single dose of dronedarone with single dose of dronedarone plus propranolol. All t_(max) values were analyzed using the non-parametric Wilcoxon's test.

Pharmacodynamics: Resting vital signs were summarized by the synthetic parameter AUC₀₋₈ and analyzed for “treatment effects and chronological (“time”) effects using repeated measures analysis of variance. Exercise vital signs were analyzed in a similar manner; the electrocardiogram exercise data were not formally analyzed and presented using descriptive statistics.

Safety: Adverse events and laboratory parameters were summarized using descriptive statistics. Individual laboratory, vital sign and electrocardiogram parameters with values outside the reference range, or markedly changed during the study compared to baseline, were highlighted.

Results

Pharmacokinetics

Trough levels (C_(bt)) of propranolol, dronedarone and SR35021 during repeated administration showed that steady-state conditions were obtained 24 hours after the first dose of propranolol and within the sixth day of administration for dronedarone. The mean (standard deviation) pharmacokinetic values are summarized below. There was no statistically significant “treatment” effect after single dosing. All propranolol parameters except t_(max) showed statistically significant “treatment” effects after repeated dosing dronedarone plus propranolol compared to propranolol alone (table 2).

TABLE 2 Propranolol Alone dronedarone + Propranolol n = 16 Repeated Repeated Parameters (units) Single Dose Dose Single Dose Dose Propranolol Day 2 Day 8 Day 26 Day 32 C_(max) (ng/ml) 59.79 (33.77) 57.68 (31.47) 68.65 (40.53) 75.38 (42.05) T_(max) (h) 2.19 (0.66) 2.26 (0.57) 2.06 (1.06) 2.00 (0.89) AUC₀₋₁₂ (ng · h/ml) 318.75 313.88 359.14 403.76 (178.62) (175.01) (188.07) (234.77) AUC_(last) (ng · h/ml) 360.85 354.73 403.30 455.06 (210.30) (214.63) (225.67) (284.21) R_(ac) — 1.00 (0.25) — 1.16 (0.20) dronedarone Alone dronedarone + Propranolol n = 16 Single Dose Day Single Dose Repeated Dose Parameters (units) 23 Day 26 Day 32 dronedarone C_(max)(ng/ml) 140.5 (59.9)  131.2 (58.3)  219.9 (104.5) t_(max) (h) 3.63 (1.37) 4.25 (1.39) 4.06 (1.57) AUC₀₋₂₄ (ng · h/ml) 983.1 (447.1) 950.9 (419.3) 1943.0 (1098.9) SR35021 C_(max)(ng/ml) 85.9 (28.8) 90.2 (32.8) 111.3 (36.1)  t_(max) (h) 5.13 (0.72) 5.13 (1.20) 4.94 (1.44) AUC₀₋₂₄ (ng · h/ml) 768.6 (278.4) 759.6 (284.7) 1295.7 (510.7) 

Pharmacodynamics

Resting electrocardiogram heart rate fell compared to baseline after repeated once daily dosing of propranolol alone (−9%), and after coadministration of dronedarone and propranolol (−6%).

The PQ interval was lengthened after repeated once daily dosing of propranolol alone (4%), and after coadministration of the two drugs (12%). The QT interval was lengthened (4%) and the QTc interval was shortened (−2%) after repeated daily dosing of propranolol alone, but after coadministration of the two drugs there was slight lengthening of these interval (4% and 1%, respectively). The T-wave amplitude increased from baseline when propranolol was administered alone (28%). The increase was reduced when the two drugs were coadministered (8%). The changes from baseline in resting electrocardiogram parameters after single oral administration of propranolol or single oral coadministration of dronedarone and propranolol were similar to those seen after repeated dosing. Single oral administration of dronedarone alone induced an increase in the PQ interval, and an increase in the T-wave amplitude from baseline.

Resting heart rate, systolic blood pressure and diastolic blood pressure fell after repeated oral administration of propranolol alone (−8%, −5% and −10%, respectively) and after coadministration with dronedarone (−4%, −8% and −12%, respectively). There was a fall in all three parameters after a single dose of propranolol (−10%, −3% and −4%, respectively) and after coadministration of the two drugs (−5%, −7% and −7%, respectively). After the single dose of dronedarone there was an increase in heart rate (2%) and a fall in systolic blood pressure (−5%) and diastolic blood pressure (−3%).

During sub-maximal exercise there was a decrease in heart rate, systolic blood pressure and diastolic blood pressure from baseline after repeated oral administration of propranolol alone (−16%, −12% and −2%, respectively) and after coadministration with dronedarone (−21%, −18% and −7%, respectively). After a single dose propranolol there was a fall in heart rate (−17%) and systolic blood pressure (−13%), but a rise in diastolic blood pressure (2%). After single coadministration of the two drugs there was a fall in all three vital signs (−18%, −18% and −2%, respectively). There was also a fall from baseline after the single dose of dronedarone (−3%, −2% and −2%, respectively). None of the changes in electrocardiogram parameters or vital signs at rest or during sub-maximal exercise were considered to be clinically relevant.

After repeated administration, the magnitude of the PR prolongation after the coadministration was 3 times greater than that observed for propranolol alone (11.9% versus 3.9%, p<0.001). The magnitude of the T-wave increase was statistically significantly lower during coadministration compared with propranolol alone (7.9% versus 28.3%, p=0.001). Based on AUC0-8 h, no difference in mean change from baseline in QT was observed between the coadministration and propranolol alone at steady state (4.4% versus 3.6%, respectively), but a statistically significant difference in mean change from baseline in QTc was observed (0.5% for coadministration versus −1.9% for propanolol alone, p<0.001), mainly linked to the reduction of HR in the dronedarone group (−6.4% versus −8.9% for propranolol). After the sub-maximal exercise test, no relevant changes in ECG parameters or vital signs were observed.

Conclusion

Repeated coadministration of 800 mg dronedarone and 80 mg propranolol significantly increased plasma concentrations of propranolol at steady-state (16% to 33%).

Single coadministration of 800 mg dronedarone and 80 mg propranolol did not modify the pharmacokinetic profile of either propranolol, dronedarone or SR35021.

The pharmacodynamic effects of propranolol or dronedarone given alone were potentiated when the two compounds were coadministered.

Dronedarone (800 mg OD) slightly increased steady-state propranolol (80 mg OD) exposure by 1.2- to 1.3-fold, which can be explained by the inhibition of CYP2D6 by dronedarone.

Beta-blockers have been used in ATHENA clinical study according to the instant invention and at the same rate in the dronedarone group and in the placebo group. About 70 to 80% of the patients had received one of these compounds during the study. Table 3 shows the numbers and percentages of patients using beta-blockers except sotalol at the inclusion in the study, whereas table 4 shows the numbers and percentages of patients who received beta-blockers except sotalol as concomitant medications during the study.

TABLE 3 Number (%) baseline selected medications-All randomized patients Dronedarone Placebo 400 mg BID Total (N = 2327) (N = 2301) (N = 4628) beta-blockers except sotalol 1641 1628 (70.8%) 3269 (70.6%) (70.5%)

TABLE 4 Number (%) of patients who received concomitant medications-All randomized patients Dronedarone Placebo 400 mg BID (N = 2327) (N = 2301) beta-blockers except sotalol 1860 (79.9%) 1785 (77.6%)

In the ATHENA trial, the object of the instant invention was used in the patients using both dronedarone and beta-blockers except sotalol. In those patients, there was no clinically significant increase of the risk of bradycardia and dronedarone has been shown to be effective for the prevention of mortality and morbidity (hospitalization) notably for the prevention of hospitalization for congestive heart failure or sudden cardiac death and the prevention of death due to stroke.

Results from ATHENA study are provided hereafter.

The relative risk (RR) was estimated using Cox's proportional-effect regression model.

The relative risk (RR) is the ratio of the rates of occurrence of a hospitalization or of a death among the patients on dronedarone, relative to the patients on placebo.

The percentage reduction x of a given event (hospitalization, death, cardiovascular death, etc.) is calculated in the following way:

x=1−relative risk.

Results Relating to the Prevention of Cardiovascular Hospitalization or Death

From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

1641 patients with beta-blockers baseline medication were part of the placebo group and 1628 patients with beta-blockers baseline medication were part of the group treated with dronedarone hydrochloride.

673 events were reported in the placebo group versus 553 in the group treated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.777, i.e. a decrease of cardiovascular hospitalization or death of 23% in patients with beta-blockers baseline medication.

Results Relating to the Prevention of Death

From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

1641 patients with beta-blockers baseline medication were part of the placebo group and 1628 patients with beta-blockers baseline medication were part of the group treated with dronedarone hydrochloride.

673 events were reported in the placebo group versus 553 in the group treated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.777, i.e. a decrease of death of 23% in patients with beta-blockers baseline medication.

Results Relating to the Prevention of Hospitalization for Congestive Heart Failure (CHF)

From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

1641 patients with beta-blockers baseline medication were part of the placebo group and 1628 patients with beta-blockers baseline medication were part of the group treated with dronedarone hydrochloride.

96 events were reported in the placebo group versus 85 in the group treated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.888, i.e. a decrease of CHF of 12% in patients with beta-blockers baseline medication.

Results Relating to the Prevention of Hospitalization for Sudden Cardiac Death

From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

1641 patients with beta-blockers baseline medication were part of the placebo group and 1628 patients with beta-blockers baseline medication were part of the group treated with dronedarone hydrochloride.

25 events were reported in the placebo group versus 9 in the group treated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.362, i.e. a decrease of sudden cardiac death of 64% in patients with beta-blockers baseline medication.

Results Relating to the Prevention of Death Due to Stroke

From the 4628 patients included in the trial, 2301 were part of the group treated with dronedarone hydrochloride.

1641 patients with beta-blockers baseline medication were part of the placebo group and 1628 patients with beta-blockers baseline medication were part of the group treated with dronedarone hydrochloride.

11 events were reported in the placebo group versus 10 in the group treated with dronedarone hydrochloride.

Calculated relative risk was equal to 0.909, i.e. a decrease of death due to stroke of 10% in patients with beta-blockers baseline medication. 

What is claimed is:
 1. A method of providing dronedarone or pharmaceutically acceptable salt or ester thereof, wherein said dronedarone or pharmaceutically acceptable salt or ester thereof is provided along with information indicating that it is useful for treating patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted to reduce the risk of cardiovascular hospitalization, and in case said patients also receive a beta-blockers treatment, the following steps should be observed: a—initiate beta-blockers treatment at a low dose; b—performing ECG verification of good tolerability; c—increase of beta-blockers dose only if results in step b) are satisfying.
 2. The method according to claim 1, wherein the pharmaceutically acceptable salt of dronedarone is hydrochloride.
 3. The method according to claim 1, wherein the information comprises printed matter that advises that dronedarone or pharmaceutically acceptable salt or ester thereof is useful for treating patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted to reduce the risk of cardiovascular hospitalization, and in case said patients also receive a beta-blockers treatment, the following steps should be observed: a—initiate beta-blockers treatment at a low dose; b—performing ECG verification of good tolerability; c—increase of beta-blockers dose only if results in step b) are satisfying.
 4. A method of promoting the use of dronedarone or pharmaceutically acceptable salts or esters thereof, the method comprising the step of conveying to a recipient at least one message comprising dronedarone or pharmaceutically acceptable salt or ester thereof is useful for treating patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted to reduce the risk of cardiovascular hospitalization, and in case said patients also receive a beta-blockers treatment, the following steps should be observed: a—initiate beta-blockers treatment at a low dose; b—performing ECG verification of good tolerability; c—increase of beta-blockers dose only if results in step b) are satisfying.
 5. The method according to claim 4, wherein the pharmaceutically acceptable salt of dronedarone is hydrochloride.
 6. An article of manufacture comprising a) a packaging material; b) dronedarone or pharmaceutically acceptable salt or ester thereof or, and c) a label or package insert contained within the packaging material indicating that: i) dronedarone or pharmaceutically acceptable salt or ester thereof is indicated in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted to reduce the risk of cardiovascular hospitalization, and ii) in case said patients also expect to receive a beta-blockers treatment, the following steps should be observed: a—initiate beta-blockers treatment at a low dose; b—performing ECG verification of good tolerability; c—increase of beta-blockers dose only if results in step b) are satisfying.
 7. An article according to claim 6, wherein the pharmaceutically acceptable salt of dronedarone is hydrochloride.
 8. A package comprising dronedarone or pharmaceutically acceptable salt or ester thereof and a label, said label comprising a printed statement which informs a prospective user that: i) dronedarone or pharmaceutically acceptable salt or ester thereof is indicated in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted to reduce the risk of cardiovascular hospitalization, and ii) in case said patients also receive a beta-blockers treatment, the following steps should be observed: a—initiate beta-blockers treatment at a low dose; b—performing ECG verification of good tolerability; c—increase of beta-blockers dose only if results in step b) are satisfying.
 9. A package according to claim 8, wherein the pharmaceutically acceptable salt of dronedarone is hydrochloride.
 10. A method for administering a combination of a beta blocker and dronedarone or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein said method comprises the following steps: a—initiating beta-blockers treatment at a low dose; b—performing ECG verification of good tolerability; and c—increasing beta-blocker dose only if results in step b) are satisfying.
 11. The method according to claim 10, wherein the pharmaceutically acceptable salt of dronedarone is hydrochloride.
 12. The method according to claim 1, wherein the beta-blocker is metoprolol or propranolol.
 13. The method according to claim 4, wherein the beta-blocker is metoprolol or propranolol.
 14. The method according to claim 10, wherein the beta-blocker is metoprolol or propranolol. 